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Continuous manufacturing is an important element of future manufacturing solutions enabling for both high product quality and streamlined development process. The increasing possibilities with computer simulations allow for innovating novel mixing principles applicable for continuous manufacturing. However, these innovative ideas based on simulations need experimental validation. The use of rapid prototyping based on additive manufacturing opens a possibility to evaluate these ideas at a low cost. In this study, a novel powder mixing geometry was prototyped using additive manufacturing and further, interfaced with an in-line near-IR spectrometer allowing for investigating the residence time distribution (RTD) in this geometry.

Successful implementation of continuous manufacturing processes requires robust methods to assess and control product quality in a real-time mode. In this study, the residence time distribution of a continuous powder mixing process was investigated via pulse tracer experiments using near infrared spectroscopy for tracer detection in an in-line mode. The residence time distribution was modeled by applying the continuous stirred tank reactor in series model for achieving the tracer (paracetamol) concentration profiles. Partial least squares discriminant analysis and principal component analysis of the near infrared spectroscopy data were applied to investigate both supervised and unsupervised chemometric modeling approaches. Additionally, the mean residence time for three powder systems was measured with different process settings. It was found that a significant change in the mean residence time occurred when comparing powder systems with different flowability and mixing process settings. This study also confirmed that the partial least squares discriminant analysis applied as a supervised chemometric model enabled an efficient and fast estimate of the mean residence time based on pulse tracer experiments.

Detection of the solid-state forms of pharmaceutical compounds is important from the drug performance point of view. Low-frequency Raman (LFR) spectroscopy has been demonstrated to be very sensitive in detecting the different solid-state forms of pharmaceutically relevant compounds. The potential of LFR spectroscopy to probe the in situ isothermal dehydration was studied using piroxicam monohydrate (PXM) and theophylline monohydrate (TPMH) as the model drugs. The dehydration of PXM and TPMH at four different temperatures (95, 100, 105, and 110 °C and 50, 60, 70, and 80 °C, respectively) was monitored in both the low- (20-300 cm

Molecular crystals with water molecules in the crystal lattice (hydrates) can radically change properties if dehydrated. The two most practically relevant pathways of dehydration can be classified as either thermally-induced or solvent-induced. The solid form transformations occurring during these processes are taking place at the surface of the particles either in the solid–gas or solid–liquid interface. In this study, it is demonstrated how atomic force microscopy (AFM) can be used to measure topography, elastic modulus and work function to elucidate differences at the crystal surface depending on the dehydration pathway. These results are performed at a single particle level, so it would be important to link the findings to the bulk powder behaviour. To address this, static charging measurements for bulk powder samples were compared with the single crystal surface measurements. The thermally-induced anhydrate acquired more charge than the monohydrate at the bulk level which could be explained by the increase in work function and surface roughness at a single particle level. The change in sign for the solvent-induced anhydrate was also in agreement with the work function. This underpins the importance of also considering microscale properties, when characterizing nanoscale structures at the surface of particulate systems.

Hydrogen peroxide vapor in detergent and pharmaceutical powders can have detrimental effects on enzymes and active ingredients. Potassium titanium oxide oxalate (PTO) adsorbed into cellulose pellets changes color upon exposure to hydrogen peroxide vapor. TGA and DVS analyses showed that cellulose dominates the interactions of PTO-loaded pellets with humidity, while the pure PTO salt can form either a mono- or dihydrate and deliquesce above 80% RH. The mono- and dihydrate forms of PTO salt gave different changes of the surface reflectance colors after exposure to hydrogen peroxide vapor. SEM-EDX and μ-CT scans showed that titanium move towards the surface of the PTO Pellets after reaction with hydrogen peroxide further affecting the surface reflectance. It is concluded that PTO-loaded pellets are suitable for detection of hydrogen peroxide vapor at an interparticle level in powders with humidity conditions in the range of 10 to 80% RH.

Density is an important material property for evaluating, or developing a tablet formulation. In-die compressibility data can be obtained using a small amount of powder with the help of a compaction simulator. However, compacts undergo volume expansion upon ejection from die. Therefore, accurate out-of-die compressibility profiles cannot be directly obtained from the in-die data. By splitting the tablet elastic recovery into three components (in-die axial, out-of-die axial, radial), we have shown that the in-die elastic recovery is linearly dependent on the compaction pressure within the range investigated, and the out-of-die elastic recovery is a material constant. Hence, we have developed a two-step data treatment (the Hirschberg-Sun approach) for deriving an accurate out-of-die compressibility profile from in-die and out-of-die data of two tablets compressed at a low and a high compaction pressure. The broad applicability of the approach was verified with a larger number of diverse materials.

The future health-care system will contain an ever expanding number of digital elements. The data stored both at a centralized health-care level and at a local, patient level (e.g., on a smartphone) will be core elements when deciding treatment strategies in a health-care scenario with Internet of things-based elements. The current way of manufacturing pharmaceutical products and related existing logistic solutions is not ready for such a revolution. One of the key challenges is cybersecurity and related robust public key infrastructure solution. This work introduces one element of a potential solution at a prototype level: the concept of cryptopharmaceuticals where pharmaceutical products are connected in a patient-specific blockchain of individual dosage units. This technology is based on the concept where each produced dosage unit has a unique information-rich pattern. A proof-of-concept smartphone application was applied to demonstrate the visualization of this blockchain at different levels. This includes the manufacturing of the individualized dosage unit, the patient view for his/her personal blockchain, and integration of these products into a health Internet of things system. This unbreakable blockchain of personal medication history will provide means to avoid counterfeit products and to enable innovative logistic solutions.

Spray drying is a well-established technology to produce inhalable dry powders. However, the amorphous nature of the particles typically obtained from the process can lead to physically and chemically unstable products. The purpose of this study was to investigate whether spray-drying could be used as a manufacturing method to produce co-amorphous drug amino acid powders with high physical stability and inhalable particulate properties. Budesonide (BUD), a compound for the treatment of lung inflammation, was co-spray-dried at a 1:1 M ratio with arginine (ARG) to produce co-amorphous powders. Two experimental factors, the solid concentration (0.85, 1.00 and 1.13%, w/v) and the ethanol concentration (55 and 75%, v/v) of the feed solution were varied to investigate the formation of co-amorphous BUD-ARG. X-ray powder diffraction (XRPD), modulated temperature differential scanning calorimetry (mDSC) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used for solid state characterization. The particle morphology, the median mass aerodynamic diameter and the aerodynamic properties of the resulting co-amorphous powders were investigated using scanning electron microscopy (SEM), an aerodynamic particle sizer (APS), and a next generation impactor (NGI), respectively. Furthermore, the physical stability of the obtained dry powder was examined. The co-spray-dried BUD-ARG samples prepared within the experimental range were predominantly amorphous. However, it was observed that while using the feed solution with both high solid and ethanol concentrations, some residual crystallinity related to budesonide was observed. The formation of co-amorphous BUD-ARG, rather than two separate amorphous phases, was confirmed by mDSC analyses. In addition, FTIR analyses indicated that hydrogen bonding occurs between the carbonyl groups of BUD and the amide groups of ARG in the co-amorphous BUD-ARG mixtures. The NGI results indicated that the particulate properties of the co-spray-dried co-amorphous BUD-ARG were at an inhalable range, with emitted doses >80%, and fine particle fractions >50%. In addition, the co-amorphous BUD-ARG was more physically stable than spray-dried BUD when stored at room temperature under dry conditions. This study demonstrated that spray drying is a useful manufacturing approach to produce physically stable co-amorphous dry powders for inhalation purposes.

In an effort to contribute to research in scalable production systems for polymeric delivery systems loaded with antimicrobial peptides (AMPs), we here investigate effects of hydrodynamic flow conditions on microfluidic particle generation. For this purpose, rapid prototyping using 3D printing was applied to prepare micromixers with three different geometric designs, which were used to prepare Ca2+-cross-linked alginate microgels loaded with the AMP polymyxin B in a continuous process. Based on fluid dynamic simulations, the hydrodynamic flow patterns in the micromixers were designed to be either (i) turbulent with chaotic disruption, (ii) laminar with convective mixing, or (iii) convective with microvortex formation. The physicochemical properties of the microgels prepared with these micromixers were characterized by photon correlation spectroscopy, laser-Doppler micro-electrophoresis, small-angle x-ray scattering, and ellipsometry. The particle size and compactness were found to depend on the micromixer geometry: From such studies, particle size and compactness were found to depend on micromixer geometry, the smallest and most compact particles were obtained by preparation involving microvortex flows, while larger and more diffuse microgels were formed upon laminar mixing. Polymyxin B was found to be localized in the particle interior and to cause particle growth with increasing peptide loading. Ca2+-induced cross-linking of alginate, in turn, results in particle contraction. The peptide encapsulation efficiency was found to be higher than 80% for all investigated micromixer designs; the highest encapsulation efficiency observed for the smallest particles generated by microvortex-mediated self-assembly. Ellipsometry results for surface-immobilized microgels, as well as results on peptide encapsulation, demonstrated electrolyte-induced peptide release. Taken together, these findings demonstrate that rapid prototyping of microfluidics using 3D-printed micromixers offers promises for continuous manufacturing of AMP-loaded microgels. Although the micromixer combining turbulent flow and microvortexes was demonstrated to be the most efficient, all three micromixer designs were found to mediate self-assembly of small microgels displaying efficient peptide encapsulation. This demonstrates the robustness of employing 3D-printed micromixers for microfluidic assembly of AMP-loaded microgels during continuous production.

Deformation is the material property that is a key for successful tablet formulation. Still, a quantitative method for assessing the change in particle size as a result of compression is lacking. The purpose of this study is to introduce a method for quantifying fragmentation after tableting. Different size fractions of dibasic calcium phosphate, microcrystalline cellulose, lactose, and starch were blended with magnesium stearate and compressed into tablets. The compressed particles were recovered from the tablets by manual grinding, which was possible by the addition of magnesium stearate. The recovered particles were subjected to scanning electron microscopy and particle size distribution (PSD) analysis. Fragmentation was quantified by characterizing the change in PSD. PSDs of the compressed samples with increasing compression pressures were analyzed, and more specifically, the particle sizes from the inflection point were used to generate a fragmentation profile. The fragmentation profiles of dibasic calcium phosphate and lactose showed extensive fragmentation during tableting; microcrystalline cellulose fragmented slightly, whereas starch did not fragment at all. The results furthermore showed that the mechanical strength of the tablet was highly dependent on fragmentation, as the mechanical strength did not start to increase before almost all fragmentation had occurred. Hence, by using this method, it is possible to quantify at which compression pressure and to which degree materials fragment during the tableting process.

Amorphous systems prepared with different strategies, such as solid dispersion with colloidal particles or soluble polymers and inclusion complex, have been used for improving solubility and dissolution of poorly water soluble drugs. The purpose of this study was to obtain a deeper understanding of the impact of three different amorphous systems prepared by spray drying with silica, polyvinylpyrrolidone (PVP) or 2-hydroxypropyl-β-cyclodextrin (HPβCD) using indomethacin (IND) as a model drug. IND was spray dried with silica, PVP or HPβCD at different mass ratios, and the obtained powders were characterized with respect to colloidal silica particle redispersion, morphology, thermal properties, solid state properties and physical stability. The solubility and intrinsic dissolution rate of IND in the different powders were assessed. It was found that all the three amorphization strategies resulted in amorphous IND product. PVP showed the best stabilizing effect on amorphous IND for at least four months while silica was the worst for no more than 18 days. The solubility of IND decreased with the decrease of HPβCD or PVP ratio in the amorphous products. Samples with HPβCD showed the highest improvement in the dissolution rate at low drug loading, i.e. 15% while samples with PVP resulted in the highest improvement of dissolution rate at high drug loading, i.e. 70%. We conclude that amorphization with PVP was the best strategy for amorphous IND stabilization among all the amorphous products investigated in this project and improved IND dissolution mostly at high drug loadings. HPβCD improved IND dissolution mostly at low drug loadings. Effect of solid dispersion with silica nanoparticles on the dissolution behavior was always the least significant among the three investigated amorphization strategies.

The aim of this study was to investigate new porous flexible substrates, i.e., solid foams that would serve as a carrier with a high ink absorption potential for inkjet printable pharmaceuticals. Propranolol hydrochloride was used as a model active pharmaceutical ingredient (API). Pharmaceutically approved and edible cellulose derivatives and gums together with different additives were evaluated as a base for the substrate. Different methods for preparation of a solid foam such as freeze-drying, vacuum oven drying and drying at room temperature were explored. Only freeze-drying of the polymeric solutions resulted in the desired porous and flexible, but mechanically stable, soft sponge-like substrates with hydroxypropyl methylcellulose (HPMC)-based solid foams being the most suitable for the use in continuous inkjet printing. The plasticized HPMC foams had a superior absorption capacity and fast penetration speed for the different solvents due to the open cell pore structure and higher porosity as compared to nonplasticized additive-free foams, although, the latter were less hygroscopic. The produced solid foams were well suited for inkjet printing of high volumes of API-containing ink. The inkjet-printed API was immediately released from the dosage forms upon contact with the dissolution medium. This work demonstrates that the fabricated solid foams, based on plasticized HPMC, show a great potential as porous carriers in the fabrication of high dose dosage forms by inkjet printing.

The rheological profile of a semi-solid product is a critical quality attribute. To monitor changes of this attribute during manufacturing, it would be beneficial to measure the rheological parameters in an on-line or in-line mode and implement this as a part of a control strategy for manufacturing of semi-solids. None of the process analytical technology (PAT) tools for measuring the rheological parameters have yet been widely accepted in the pharmaceutical area, as most of the equipment can only measure viscosity. Therefore, an automated system based on the measurement of pressure difference across both a topology optimized channel and a tube geometry (capillary viscometer) was investigated. The Pressure Difference Apparatus (PDA) can sample from the bulk intermediate/product stream and press the sample through the apparatus at different flow rates to yield a frequency sweep (G' and G″) and a flow curve (viscosity). A calibration model was successfully prepared and verified with hydroxyethyl cellulose gels with polymer content varying from 1.0 to 1.5% (w/w) resulting in gels of different viscosities. The calibration model was used on-line during manufacturing of a gel and manufacturing changes related to dilution of the product were clearly reflected in the batch evolution profiles. The measurements with the PDA reflected the shear rate and frequency ranges relevant for manufacturing and thereby complemented the rheology measurements obtained with a standard rheometer with real time data.

The dehydration process of the widely studied drug theophylline is unravelled by combining molecular dynamics simulations with powder X-ray diffraction and solid-state NMR measurements and calculations. Based on the simulation, we determine a high-energy short-lived metastable crystal form, and additionally suggest the existence of a fast-converting form.

Printing technologies, both 2D and 3D, have gained considerable interest during the last years for manufacturing of personalized dosage forms, tailored to each patient. Here we review the research work on 2D printing techniques, mainly inkjet printing, for manufacturing of film-based oral dosage forms. We describe the different printing techniques and give an overview of film-based oral dosage forms produced using them. The main part of the review focuses on the non-destructive analytical methods used for evaluation of qualitative aspects of printed dosage forms, e.g., solid-state properties, as well as for quantification of the active pharmaceutical ingredient (API) in the printed dosage forms, with an emphasis on spectroscopic methods. Finally, the authors share their view on the future of printed dosage forms.

Probabilistic modeling using influence networks is an efficient, intuitive, and easy to communicate strategy in the development of complex pharmaceutical products. This study was aimed to use a risk-based approach to explore the complex interactions between product and process design parameters affecting size and shape of the particles in injectable aqueous crystalline suspensions (ACS). Based on a risk assessment, a design of experiments (DOE) was applied to evaluate the most important parameters, i.e., four critical material attributes and two critical process parameters. A model hydrophobic drug (carbamazepine) was milled and homogenized in a multistep process (dispersion and milling steps). The final formulations were characterized with automated at-line image analysis of thousands of individual particles. The particle size and shape distributions were summarized with descriptive parameters, and the relationship of these parameters and the DOE was modeled using influence networks (INs). This approach was compared and contrasted with a classical modeling approach based on multivariate linear regression (MVLR). INs had a superior visual interpretation capability of the complex and multivariate ACS system making the risk-based decision making more accessible. The probability and causality were included in the IN, i.e., the relationships between size and shape. Moreover, IN allowed to incorporate prior knowledge in a systematic way by implementing a ‘black and white list’. An IN based model was created with the following model performance: a mean absolute percentage error of 1.7% and 1.1% for the size and 6.2% and 5.0% for the shape, respectively for dispersed and milled ACS. Parameters with the highest and lowest probability to control the critical quality attributes of ACS could be identified. Consequently, the parameter settings giving the optimum particle size and shape could be predicted using a Monte Carlo simulation to calculate the probability of success including the uncertainty of the model. The cubic MVLR model for the size of milled ACS was comparable to the IN in terms of the mean absolute percentage error, i.e., 1.1%. However, IN was more efficient in visualizing the complex and multivariate data set, including all the critical quality attributes and formulation/process parameters of the ACS at the same time. Moreover, the prior knowledge used in probabilistic modeling of IN could be systematically documented.

The typical excipients used as bulking agents and lyoprotectants for freeze-drying are usually limited to only a few selected substances, such as sucrose and mannitol. Considering the sheer diversity amongst proteins, it is doubtful that this limited choice should, in every case, provide the best possible option in order to achieve the most stable product. In this work, a screening of 12 proteins with 64 excipients was conducted in order to increase the knowledge space of potential excipients. Three critical quality attributes (CQAs) of the freeze-dried products, namely the solid state, the cake appearance and the protein integrity based on changes in tryptophan fluorescence were investigated by high throughput X-ray powder diffraction, image analysis and intrinsic fluorescence spectroscopy, respectively. It was found, that in some cases the excipient had a dominating influence on the CQAs, whilst in other cases the CQAs were primarily protein dependent, or that the CQAs were dependent on the combination of both. In the course of this investigation, a general view of potentially relevant excipients, and their interplay with various proteins, was obtained, thereby furthermore paving the way for the use of novel freeze-drying excipients.

Drug release performance of tablets is often highly dependent on disintegration, and water ingress is typically the rate-limiting step of the disintegration process. Water ingress into tablets is known to be highly influenced by the microstructure of the tablet, particularly tablet porosity. Initial particle size distribution of the formulation and the predominant powder deformation behaviour during compression are expected to impact such microstructure, making both factors important to investigate in relation to water ingress into tablets. Two size fractions (

Roll compaction/dry granulation often results in loss of tabletability. The two main hypotheses for this are granule hardening and granule size enlargement. The aim of this study was to investigate the effect of granule size, roll compaction force, and granule fragmentation upon tableting and its effect on tabletability of granules constituting a ductile or brittle material. Plastically deforming microcrystalline cellulose (MCC) and fragmenting lactose monohydrate (lactose) were roll compacted at five roll compaction forces ranging from 2 to 16 kN/cm. Granule size fractions of 250–355 and 500–710 µm were blended with 10% magnesium stearate (MgSt), compressed into tablets and ground to obtain compressed granules. The predominant deformation behaviour of the particles constituting the granules directly impacted granule deformation upon tableting, as lactose granules fractured extensively upon tableting, whereas MCC granules predominantly deformed by plastic deformation. Increased roll compaction force resulted in more granule hardening of both materials and thereby granules less susceptible to fragmentation upon tableting. Granule hardening accounted for the largest loss of tabletability of MCC granules upon roll compaction. Roll compaction force and granule size had no or negligible effect on tabletability of lactose tablets without MgSt, whereas increased roll compaction force and larger granules decreased tensile strength of tablets containing lactose granules blended with MgSt. This was explained by inter-particle and inter-granular bonds contributing equally to the tensile strength of lactose tablets without MgSt. However, after addition of MgSt, the decreased fragmentation tendency of larger granules compacted at higher roll compaction forces resulted in greater MgSt coverage of the granules upon tableting, thereby decreasing tabletability.

Mimicking the human decision-making process is challenging. Especially, many process control situations during the manufacturing of pharmaceuticals are based on visual observations and related experience-based actions. The aim of the present work was to investigate the use of image analysis to classify the quality of coated tablets. Tablets with an increasing amount of coating solution were imaged by fast scanning using a conventional office scanner. A segmentation routine was implemented to the images, allowing the extraction of numeric image-based information from individual tablets. The image preprocessing was performed prior to utilization of four different classification techniques for the individual tablet images. The support vector machine (SVM) technique performed superior compared to a convolutional neural network (CNN) in relation to computational time, and this approach was also slightly better at classifying the tablets correctly. The fastest multivariate method was partial least squares (PLS) regression, but this method was hampered by the inferior classification accuracy of the tablets. Finally, it was possible to create a numerical threshold classification model with an accuracy comparable to the SVM approach, so it is evident that there exist multiple valid options for classifying coated tablets.

Medical cannabis has shown to be effective in various diseases that have not successfully been treated with other marketed drug products. However, the dose of cannabis is highly individual and additionally, medical cannabis is prone to misuse. To combat these challenges, the concept of data-enriched edible pharmaceuticals (DEEP) is introduced. Quick Response (QR) code patterns containing lipophilic cannabinoids, i.e., cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), were printed using a desktop inkjet printer. This allows for simultaneously printing an individual dose and encapsulating information relevant to the end-users and other stakeholders in a single dosage unit, which is readable by a standard smartphone. Different doses of CBD and THC were incorporated in the DEEP by printing various (1–10) layers of the cannabinoid-containing ink on porous substrates, i.e., solid foams, prepared by solvent casting and subsequent freeze-drying. The printed DEEP were still readable after 8 weeks of storage in dry and cold conditions. This approach of ‘in-drug labeling’ instead of ‘drug package labeling’ provides a new possibility for developing a more efficient supply chain of pharmaceuticals and safer medication schemes by increasing the traceability of drug products at a single dosage unit level.

Material deformation behaviour has a critical impact on tablet formation. Fragmentation is one of the key mechanisms affecting the strength of a final compact, however, quantitative methods for estimating fragmentation are often complex, destructive and time-consuming. The purpose of this study was to investigate the applicability of terahertz time-domain spectroscopy (THz-TDS) to quantify fragmentation upon tableting. Up to five size fractions of microcrystalline cellulose (MCC), dibasic calcium phosphate (DCP), and lactose monohydrate (lactose) in the range of

The potential of fused filament fabrication (FFF) for the administration of active pharmaceutical compounds is a recent approach to develop complex and custom-made drug delivery systems (DDSs). However, the FFF technology is characterized by certain limitations, which are associated with the nature of the process, i.e., the required mechanical properties of the feedstock, as well as the thermal stability of the incorporated polymers, excipients and active compounds. Thus, hybrid DDSs have been recently introduced, to overcome these boundaries. The concept of these systems is defined by the effective coupling of FFF with conventional manufacturing technologies, as a novel pathway to expand the available pool of raw materials and pharmaceutical applications of FFF.

In the area of developing oromucosal drug delivery systems, mucoadhesive buccal films are the most promising formulations for either systemic or local drug delivery. The current study presents the fabrication of buccal films, by combining fused deposition modeling (FDM) and inkjet printing. Hydroxypropyl methylcellulose-based films were fabricated via FDM, containing the non-steroidal anti-inflammatory drug ketoprofen. Unidirectional release properties were achieved, by incorporating an ethyl cellulose-based backing layer. The local anesthetic lidocaine hydrochloride, combined with the permeation enhancer l-menthol, was deposited onto the film by inkjet printing. Physicochemical analysis showed alterations in the characteristics of the films, and the mucoadhesive and mechanical properties were effectively modified, due to the ink deposition on the substrates. The in vitro release data of the active pharmaceutical compounds, as well as the permeation profiles across ex vivo porcine buccal mucosa and filter-grown TR146 cells of human buccal origin, were associated with the presence of the permeation enhancer and the backing layer. The lack of any toxicity of the fabricated films was demonstrated by the MTT viability assay. This proof-of-concept study provides an alternative formulation approach of mucoadhesive buccal films, intended for the treatment of local oromucosal diseases or systemic drug delivery.

Thermal methods are indispensable for the characterization of most materials. However, the existing methods require bulk amounts for analysis and give an averaged response of a material. This can be especially challenging in a biomedical setting, where only very limited amounts of material are initially available. Nano- and microelectromechanical systems (NEMS/MEMS) offer the possibility of conducting thermal analysis on small amounts of materials in the nano-microgram range, but cleanroom fabricated resonators are required. Here, we report the use of single drug and collagen particles as micro mechanical resonators, thereby eliminating the need for cleanroom fabrication. Furthermore, the proposed method reveals additional thermal transitions that are undetected by standard thermal methods and provide the possibility of understanding fundamental changes in the mechanical properties of the materials during thermal cycling. This method is applicable to a variety of different materials and opens the door to fundamental mechanistic insights., Eliminating the need for cleanroom fabrication for thermomechanical characterization of organic samples in a biomedical setting remains a challenge. Here, the authors propose the use of a single drug and collagen particles as resonators, enabling direct measurements on a material during thermal cycling.

The specific aim in this study was to understand the effect of critical process parameters on the solid form composition of model drug compounds during hot melt extrusion using in-line Raman spectroscopy combined with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) modeling for semi-quantitative kinetic profiling. It was observed that the hydrate and anhydrate solid forms of two model drugs in the melts of nitrofurantoin (NF):polyethylene oxide (PEO) and piroxicam (PRX):PEO could be resolved from a MCR-ALS model without an external calibration dataset. Based on this model, the influence of two critical process parameters (shear and temperature) on the solid form composition could be evaluated in a real-time mode and the kinetics of complex transformation pathways could be explored. Additionally, the dehydration pathways of NF monohydrate and PRX monohydrate in molten PEO could be derived. It can be concluded that dehydration of both hydrates in PEO occurs via competing mechanisms&mdash, a solution-mediated transformation pathway and a solid&ndash, solid transformation, and that the balance between these mechanisms is determined by the combined effect of both temperature and shear. Another important observation was that the water released from these hydrate compounds has a detectable effect on the rheological characteristics of this mixture.

Asthma is a prevalent lung disorder that cause heavy burdens globally. Inhalation medicaments can relieve symptoms, improve lung function and, thus, the quality of life. However, it is well-documented that patients often do not get the prescribed dose out of an inhaler and the deposition of drug is suboptimal, due to incorrect handling of the device and wrong inhalation technique. This study aims to design and fabricate an acoustic dry powder inhaler (ADPI) for monitoring inhalation flow and related drug administration in order to evaluate whether the patient receives the complete dose out of the inhaler. The devices were fabricated using 3D printing and the impact of the acoustic element geometry and printing resolution on the acoustic signal was investigated. Commercial Foradil (formoterol fumarate) capsules were used to validate the availability of the ADPI for medication dose tracking. The acoustic signal was analysed with Partial-Least-Squares (PLS) regression. Indicate that specific acoustic signals could be generated at different air flow rates using a passive acoustic element with specific design features. This acoustic signal could be correlated with the PLS model to the air flow rate. A more distinct sound spectra could be acquired at higher printing resolution. The sound spectra from the ADPI with no capsule, a full capsule and an empty capsule are different which could be used for medication tracking. This study shows that it is possible to evaluate the medication quality of inhaled medicaments by monitoring the acoustic signal generated during the inhalation process.

Rapid prototyping based on in silico design and 3D printing enables fast customization of complex geometries to multiple needs. This study utilizes, additive manufacturing for rapid prototyping of elements for continuously operating mixing geometries including interfaces with process analytical technology (PAT) tools, to show that 3D printing can be used for prototyping of both parts of production line and PAT interfacing solution. An additional setup was designed for measuring the dynamic calibration samples for a semi-quantitative near infrared (NIR) spectroscopic model. The powder was filled in a small calibration chamber and in-line NIR spectra of calibration samples were collected from moving material while mimicking the powder flow dynamics in a typical continuous mixer. This dynamic powder mixing system was compared with a static powder calibration model where the NIR probe was placed at different positions on a static sample. Principal component analysis (PCA) revealed that the 3D printed device with dynamic measurement of the NIR spectra had more potential for quantitative analysis. With the prototype continuous mixer, two differently placed process interfaces for NIR spectroscopic monitoring of the powder mixing were evaluated. With this approach, the importance of positioning the process analytical tools to assess the blend uniformity could be demonstrated. It was also observed that with the longer mixing geometry, a better mixing result was achieved due to a larger hold up volume and increased residence time., Graphical abstract Image, graphical abstract

A challenge in the dry granulation (DG) process is the generation of an excessive amount of fines during milling, which can cause problems in die filling due to poor flowability and content uniformity of tablets. Using a design of experiments (DOE) approach, we show that the amount of fines generated during milling decreases with either increasing ribbon density or screen size, while impeller speed has negligible effect. Moreover, under identical milling conditions, the percent fines can be accurately predicted from ribbon density. Thus, controlling ribbon density and screen size is important for optimizing the amount of fines produced during DG process. Because density has a central role in the outcome, it is a critical ribbon property that needs to be controlled to improve robustness of the DG process.

Poly(lactic- co-glycolic acid) (PLGA) microparticles represent a promising formulation approach for providing steady pharmacokinetic/pharmacodynamic profiles of therapeutic drugs for a long period. Understanding and controlling the supramolecular structure of PLGA microparticles at a molecular level is a prerequisite for the rational design of well-controlled, reproducible sustained-release profiles. Herein, we reveal the role of PLGA molecular conformation in particle formation and drug release. The nanoscale network of PLGA microparticles spray-dried using the solvents with distinct polarities was investigated by using NMR and neutron scattering. By employing chemometric method, we further demonstrate the evolution of nanoscale networks in spray-dried PLGA microparticles upon water absorption. Our results indicate that PLGA molecules form more chain entanglements during spray drying when using the solvents with low polarity, where PLGA molecule adopts a more flexible, extended conformation, resulting in the network being more resistant to water absorption in spray-dried PLGA microparticles. This work underlines the role of PLGA molecular conformation in controlling formation and evolution of nanoscale network of spray-dried PLGA microparticles and will have important consequences in achieving customized drug release from the PLGA microparticles.

Small interfering RNA (siRNA) is regarded as one of the most powerful tools for the treatment of various diseases by downregulating the expression of aberrant proteins. Delivery vehicle is often necessary for getting siRNA into the cells. Nanocomplex using polyamidoamine (PAMAM) is regarded a promising approach for the delivery of siRNA. The size of siRNA nanocomplexes is a critical attribute in order to achieve high gene silencing efficiency in vivo. Microfluidics provides advantages in the preparation of siRNA nanocomplexes due to better reproducibility and a potential for more robust process control. The mixing efficiency of siRNA and PAMAM is different in microfluidics systems with different geometries, therefore, resulting in nanocomplexes with varying size attributes. In this study, hydrodynamic flow focusing microfluidic chips with different channel designs, i.e. diameters/widths, channel shapes (cylindrical/rectangular) and inter-channel spacings were optimized in silico and rapidly prototyped using 3D printing and finally, used for production of siRNA nanocomplexes. The fluid mixing inside the microfluidic chips was simulated using the finite element method (FEM) with the single-phase laminar flow interface in connection with the transport of diluted species interface. The digital design and optimization of microfluidic chips showed consistency with experimental results. It was concluded that the size of siRNA nanocomplexes can be controlled by adjusting the channel geometry of the microfluidic chips and the simulation with FEM could be used to facilitate the design and optimization of microfluidic chips in order to produce nanocomplexes with desirable attributes.

Thermal conductivity is a material specific property, which influences many aspects of pharmaceutical development, such as processing, modelling, analysis, and the development of novel formulation approaches. We have presented a method to measure thermal conductivity of small molecule organic glasses, based on a vacuum molding sample preparation technique combined with modulated differential scanning calorimetry. The method is applied to the two amorphous model compounds indomethacin and celecoxib. The measured values of below 0.2 W/m °C indicate very low thermal conductivity of the amorphous compounds, within the range of organic liquids and low conducting polymers.

Adopting the Quality by Design (QbD) approach in the drug development process has transformed from "nice-to-do" into a crucial and required part of the development, ensuring the quality of pharmaceutical products throughout their whole life cycles. This review is discussing the implementation of the QbD thinking into the production of long-acting injectable (LAI) PLGA/PLA-based microspheres for the therapeutic peptide and protein drug delivery. Various key elements of the QbD approaches are initially elaborated using Bydureon®, a commercial product of LAI PLGA/PLA-based microspheres, as a classical example. Subsequently, the factors influencing the release patterns and the stability of the peptide and protein drugs are discussed. This is followed by a summary of the state-of-the-art of manufacturing LAI PLGA/PLA-based microspheres and the related critical process parameters (CPPs). Finally, a landscape of generic product development of LAI PLGA/PLA-based microspheres is reviewed including some major challenges in the field.

Many active pharmaceutical ingredients exhibit a needle-like (acicular) crystal habit, which can significantly complicate their downstream processing. In this study, the acicular crystal habit of a model active pharmaceutical ingredient, 5-aminosalicylic acid (5-ASA), was modified by addition of selected organic solvents to the typical aqueous crystallization process. 5-ASA was crystallized by a pH shift from 7.5-8 to 4 in the presence of methanol, acetonitrile, acetone, tetramethylurea, tetrahydrofuran or dimethyl sulfoxide at 25% v/v, or butanol at 9% v/v. Changes to the experimentally observed crystal habit are rationalized by considering adsorption energy calculations for the solvent molecules onto the morphologically important crystal faces. The crystal habit was influenced most significantly by organic solvents containing a good H-bond acceptor atom, particularly oxygen in acetone, tetramethylurea, tetrahydrofuran, and dimethyl sulfoxide. Such solvents have strongly stabilizing adsorption energies onto the fast-growing crystal faces, and their presence in solution thereby serves to modify the acicular habit of 5-ASA. The developed knowledge base on crystal interface-solvent interactions can form a basis for further engineering of an optimal crystal habit for 5-ASA.

Traditionally, the development of a new solid dosage form is formulation-driven and less focus is put on the design of a specific microstructure for the drug delivery system. However, the compaction process particularly impacts the microstructure, or more precisely, the pore architecture in a pharmaceutical tablet. Besides the formulation, the pore structure is a major contributor to the overall performance of oral solid dosage forms as it directly affects the liquid uptake rate, which is the very first step of the dissolution process. In future, additive manufacturing is a potential game changer to design the inner structures and realise a tailor-made pore structure. In pharmaceutical development the pore structure is most commonly only described by the total porosity of the tablet matrix. Yet it is of great importance to consider other parameters to fully resolve the interplay between microstructure and dosage form performance. Specifically, tortuosity, connectivity, as well as pore shape, size and orientation all impact the flow paths and play an important role in describing the fluid flow in a pharmaceutical tablet. This review presents the key properties of the pore structures in solid dosage forms and it discusses how to measure these properties. In particular, the principles, advantages and limitations of helium pycnometry, mercury porosimetry, terahertz time-domain spectroscopy, nuclear magnetic resonance and X-ray computed microtomography are discussed.

The additive manufacturing industry achieved a corporate annual growth rate of 25.9% according to the Forbes analysis of the Wohlers Report 2016. This high growth rate is placed in perspective when looking at the past 27 years where the corporate annual growth rate has averaged 26.2% each year indicating that additive manufacturing is clearly a growing industry. Such growth needs to be supported by suitable quality testing methods: with the economic success achieved in this market and the associated transition from mass production toward mass customization comes the need for new and innovative methods to assess the quality of the 3D printed geometries. This will be especially important for pharmaceutical products where a sub-standard quality of the final product can have detrimental consequences for patient health and safety. [Formula: see text]

Formulation composition and processing conditions can be adjusted to enhance the structural integrity as well as the bioactivity of proteins in the spray drying process. In this study, lysozyme was chosen as a model pharmaceutical protein to study these aspects when spray drying from water-ethanol mixtures. The effect of formulation additives (trehalose, Tween 20 and phosphate-buffered saline) and processing conditions (inlet temperature and storage time of lysozyme in the feed solution before the spray drying process) on the protein bioactivity was investigated. The results showed that the bioactivities of spray dried lysozyme with these additives were about 5–10% higher than that without additives. The bioactivity of the spray dried lysozyme was found to increase with a decrease in the inlet temperature from 130 °C to 80 °C, with similar findings when shortening the storage time of the feed solutions prior to spray drying. Fourier Transform Infrared (FTIR) and Circular Dichroism (CD) results showed that the native structures of lysozyme were largely restored upon reconstitution of the spray dried powder in water after the spray drying process. This suggests that the bioactivity of lysozyme could be preserved adequately by optimization of both the formulation composition and process conditions even when spray drying from a water-ethanol mixture.

The design and production of an oral dual-compartmental dosage unit (dcDU) was examined in vitro and in vivo with the purpose of physically isolating and modulating the release profile of an anti-tuberculosis drug combination. Rifampicin (RIF) and isoniazid (ISO) are first line combination drugs for treatment of tuberculosis (TB) that negatively interact with each other upon simultaneous release in acidic environment. The dcDUs were designed in silico by computer aided design (CAD) and fabricated in two steps; first three-dimensional (3D) printing of the outer structure, followed by hot-melt extrusion (HME) of the drug-containing filaments. The structure of the fabricated dcDUs was visualized by scanning electron microscopy (SEM). The 3D printed compartmentalized shells were loaded with filaments containing active pharmaceutical ingredient (API) and selectively sealed to modulate drug dissolution. The drug release profile of the dcDUs was characterized by pH-transfer dissolution in vitro and pharmacokinetics studies in rats, and resulted in modified release of the APIs from the dcDUs as compared to the free filaments. Furthermore, the selective physical sealing of the compartments resulted in an effective retardation of the in vitro API release. The findings of this study support the development of controllable-by-design dcDU systems for combination therapies to enable efficient therapeutic translation of oral dosage forms.

Porous implants or implantable scaffolds used for tissue regeneration can encourage tissue growth inside the implant and provide extended drug release. Water-soluble polymers incorporated into a biodegradable or inert implant matrix may leach out upon contact with biological fluids and thereby gradually increasing the porosity of the implant and simultaneously release drug from the implant matrix. Different molecular weight grades of methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) were mixed with polylactide and extruded into model implants containing nitrofurantoin as a model drug. The effect of the leached pore formers on the implant porosity and the rheology of the implant microenvironment in vitro was investigated and it was shown that HPMC pore formers had the greatest effect on the surrounding viscosity, with higher drug release and pore forming ability as compared to the MC pore formers. The highest molecular weight HPMC led to the most significant increase in viscosity of the implant microenvironment, while the highest drug release was achieved with the lowest molecular weight HPMC. The data suggested that the microenvironmental rheology of the implant, both in the formed pores and in biological fluids in the immediate vicinity of the implant could be an important factor affecting the diffusion of the drug and other molecules in the implantation site.

There is an increasing need to provide more detailed insight into the behavior of particulate systems. The current powder characterization tools are developed empirically and in many cases, modification of existing equipment is difficult. More flexible tools are needed to provide understanding of complex powder behavior, such as mixing process and segregation phenomenon. An approach based on the fast prototyping of new powder handling geometries and interfacing solutions for process analytical tools is reported. This study utilized 3D printing for rapid prototyping of customized geometries; overall goal was to assess mixing process of powder blends at small-scale with a combination of spectroscopic and mechanical monitoring. As part of the segregation evaluation studies, the flowability of three different paracetamol/filler-blends at different ratios was investigated, inter alia to define the percolation thresholds. Blends with a paracetamol wt% above the percolation threshold were subsequently investigated in relation to their segregation behavior. Rapid prototyping using 3D printing allowed designing two funnels with tailored flow behavior (funnel flow) of model formulations, which could be monitored with an in-line near-infrared (NIR) spectrometer. Calculating the root mean square (RMS) of the scores of the two first principal components of the NIR spectra visualized spectral variation as a function of process time. In a same setup, mechanical properties (basic flow energy) of the powder blend were monitored during blending. Rapid prototyping allowed for fast modification of powder testing geometries and easy interfacing with process analytical tools, opening new possibilities for more detailed powder characterization.

This study presents an evaluation of the predicted and experimentally observed flow behavior, i.e., flow pattern and critical outlet diameter, in a tablet press hopper. Three grades of a commonly used pharmaceutical additive, microcrystalline cellulose, were used for this purpose. The prediction of the flow behavior was made by first extrapolating shear and wall friction data and, subsequently, applying these extrapolation-based data as input variables to Jenike's hopper design method. Predictions were then compared with empirical discharge experiments from a tablet press hopper and a funnel with varying outlet diameters. By application of a mixed-effect 2nd order polynomial model for the extrapolation of the wall yield locus, accurate flow pattern predictions for the tablet press hopper was made. However, the observed flow patterns were very sensitive to the powders' moisture content. The comparison of the observed and predicted critical outlet diameters showed good agreement for the powder with the best flowability when linear extrapolation of the flow function was applied. In contrast, the predicted critical outlet diameter was slightly overestimated compared to the experimentally observed diameter for the two more cohesive powders. A likely reason for this overestimation is that the flow function probably has a non-linear convex upward shape for these two powders at very small consolidation stresses. These findings illustrate the relevance of measuring shear and wall shear stresses at very small consolidation stresses to improve the flow behavior predictions for small-scale process equipment typically used during production of solid state pharmaceuticals.

Many future drug products will be based on innovative manufacturing solutions, which will increase the need for a thorough understanding of the interplay between drug material properties and processability. In this study, hot melt extrusion of a drug-drug mixture with minimal amount of polymeric excipient was investigated. Using indomethacin-cimetidine as a model drug-drug system, processability of physical mixtures with and without 5% (w/w) of polyethylene oxide (PEO) were studied using Differential Scanning Calorimetry (DSC) and Small Amplitude Oscillatory Shear (SAOS) rheometry. Extrudates containing a co-amorphous glass solution were produced and the solid-state composition of these was studied with DSC. Rheological analysis indicated that the studied systems display viscosities higher than expected for small molecule melts and addition of PEO decreased the viscosity of the melt. Extrudates of indomethacin-cimetidine alone displayed amorphous-amorphous phase separation after 4 weeks of storage, whereas no phase separation was observed during the 16 week storage of the indomethacin-cimetidine extrudates containing 5% (w/w) PEO. Melt extrusion of co-amorphous extrudates with low amounts of polymer was found to be a feasible manufacturing technique. Addition of 5% (w/w) polymer reduced melt viscosity and prevented phase separation.

Hot melt extrusion is important for the development of advanced pharmaceutical dosage forms. In this study, the dehydration of nitrofurantoin monohydrate during melt extrusion below the expected dehydration temperature has been investigated. The influence of process time, temperature, and drug/polymer ratio on the solid form of the drug compound was studied using drug/polymer physical mixtures with thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction, rheometry, and hot-stage microscopy and compared with data generated from the extruded products. Extensive dehydration of nitrofurantoin monohydrate was surprisingly observed at extrusion temperatures as low as 70 °C in contrast with TGA and DSC analysis of the pure drug indicating dehydration onset at around 90 °C. This was related to shear induced solution-mediated transformation, where nitrofurantoin dissolved into the molten polymer and rapidly recrystallized as nitrofurantoin anhydrate, as well as simultane...

A quantitative structure-property relationship (QSPR) between protein stability and the physicochemical properties of excipients was investigated to enable a more rational choice of stabilizing excipients than prior knowledge. The thermal transition temperature and aggregation time were determined for lysozyme in combination with 13 different amino acids using high throughput fluorescence spectroscopy and kinetic static light scattering measurements. On the theoretical side, around 200 2D and 3D molecular descriptors were calculated based on the amino acids’ chemical structure. Multivariate data analysis was applied to correlate the descriptors with the experimental results. It was possible to identify descriptors, i.e. amino acids properties, with a positive influence on either transition temperature or aggregation onset time, or both. A high number of hydrogen bond acceptor moieties was the most prominent stabilizing factor for both responses, whereas hydrophilic surface properties and high molecular mass density mostly had a positive influence on the unfolding temperature. A high partition coefficient (logP(o/w)) was identified as the most prominent destabilizing factor for both responses. The QSPR shows good correlation between calculated molecular descriptors and the measured stabilizing effect of amino acids on lysozyme., final draft, peerReviewed

Efficient downstream processing of active pharmaceutical ingredients (APIs) can depend strongly on their particulate properties, such as size and shape distributions. Especially in drug products with high API content, needle-like crystal habit of an API may show compromised flowability and tabletability, creating significant processability difficulties on a production scale. However, such a habit can be adapted to the needs of downstream processing. To this end, we modified the needle-like crystal habit of the model API 5-aminosalicylic acid (5-ASA). This study reports processability assessment of six representative crystal habits of 5-ASA (needles, plates, rectangular bars, rhombohedrals, elongated hexagons, and spheroids) in the context of direct compression using ring shear tester, flow rate analyzer, and instrumented tablet press. As expected, needles were very cohesive, had low flow rate (1.0 ± 0.08 mg/s), and low bulk density (0.14 ± 0.01 g/mL) but showed better tabletability, whereas the opposite w...

The purpose of this study was to investigate the applicability of Raman spectroscopy for visualization and quantification of inkjet-printed pharmaceuticals. Haloperidol was used as a model active pharmaceutical ingredient (API), and a printable ink base containing lactic acid and ethanol was developed. Inkjet printing technology was used to apply haloperidol ink onto three different substrates. Custom-made inorganic compacts and dry foam, as well as marketed paracetamol tablets were used as the substrates. Therapeutic personalized doses were printed by using one to ten printing rounds on the substrates. The haloperidol content in the finished dosage forms were determined by high-performance liquid chromatography (HPLC). The distribution of the haloperidol on the dosage forms were visualized using Raman chemical imaging combined with principal components analysis (PCA). Raman spectroscopy combined with modeling by partial least squares (PLS) regression was used for establishment of a quantitative model of the haloperidol content in the printed dosage forms. A good prediction of the haloperidol content was achieved for the inorganic compacts, while a slightly poorer prediction was observed for the paracetamol tablets. It was not possible to quantify haloperidol on the dry foam due to the low and varying density of the substrate. Raman spectroscopy is a useful tool for visualization and quality control of inkjet printed personalized medicine.

Solid-state transitions at the surface of pharmaceutical solid dosage forms (SDF) were monitored using multi-series hyperspectral imaging (HSI) along with Multivariate Curve Resolution – Alternating Least Squares (MCR-ALS) and Parallel Factor Analysis (PARAFAC and PARAFAC2). First, the solid-state transformation due to the dehydration of the monohydrate forms of piroxicam and lactose to their respective anhydrate counterparts in tablets were monitored using temperature series NIR-HSI. PARAFAC and MCR-ALS solutions were hampered by the lack of strict trilinearity of the pixels among the unfolded series NIR-images (three-way array) and due to rotational ambiguity (augmented matrix), respectively, while PARAFAC2 resolved satisfactorily the profile of the corresponding compounds in the pixels in the series NIR-images. Next, the amorphous-to-crystalline transitions were monitored in solid dispersion of indomethacin with polyvinylpyrrolidone using time series MIR-HSI. MCR-ALS properly resolved the known solid-state forms of the drug in the pixels of the series MIR-images, while PARAFAC and PARAFAC2 failed to properly resolve all the drug forms in the series MIR-images due to i) strict trilinearity leak in the three-way array and ii) the mandatory constant cross-product AkTAk over the k series MIR-images (A is the loadings of the shift mode), respectively. The highlighting of the advantages and limitation of the corresponding curve resolution methods stressed their potential applicability when handling multi-series HSI to study solid-state transitions in pharmaceutical SDFs.

Molecular dynamics (MD) simulations have evolved to an increasingly reliable and accessible technique and are today implemented in many areas of biomedical sciences. We present a generally applicable method to study dehydration of hydrates based on MD simulations and apply this approach to the dehydration of ampicillin trihydrate. The crystallographic unit cell of the trihydrate is used to construct the simulation cell containing 216 ampicillin and 648 water molecules. This system is dehydrated by removing water molecules during a 2200 ps simulation, and depending on the computational dehydration rate, different dehydrated structures were observed. Removing all water molecules immediately and removing water relatively fast (10 water molecules/10 ps) resulted in an amorphous system, whereas relatively slow computational dehydration (3 water molecules/10 ps) resulted in a crystalline anhydrate. The structural changes could be followed in real time, and in addition, an intermediate amorphous phase was identified. The computationally identified dehydrated structure (anhydrate) was slightly different from the experimentally known anhydrate structure suggesting that the simulated computational structure could represent a kinetically trapped dehydration intermediate.

Hot-melt extrusion and 3D printing are enabling manufacturing approaches for patient-centred medicinal products. Hot-melt extrusion is a flexible and continuously operating technique which is a crucial part of a typical processing cycle of printed medicines. In this work we use hot-melt extrusion for manufacturing of medicinal films containing indomethacin (IND) and polycaprolactone (PCL), extruded strands with nitrofurantoin monohydrate (NFMH) and poly (ethylene oxide) (PEO), and feedstocks for 3D printed dosage forms with nitrofurantoin anhydrate (NFAH), hydroxyapatite (HA) and poly (lactic acid) (PLA). These feedstocks were printed into a prototype solid dosage form using a desktop 3D printer. These model formulations were characterized using near-infrared chemical imaging (NIR-CI) and, more specifically, the image analytical data were analysed using multivariate curve resolution-alternating least squares (MCR-ALS). The MCR-ALS algorithm predicted the spatial distribution of IND and PCL in the films with reasonable accuracy. In the extruded strands both the chemical mapping of the components in the formulation as well as the solid form of the active compound could be visualized. Based on the image information the total nitrofurantoin and PEO contents could be estimated., The dehydration of NFMH to NFAH, a process-induced solid form change, could be visualized as well. It was observed that the level of dehydration increased with increasing processing time (recirculation during the mixing phase of molten PEO and nitrofurantoin). Similar results were achieved in the 3D printed solid dosage forms produced from the extruded feedstocks. The results presented in this work clearly demonstrate that NIR-CI in combination with MCR-ALS can be used for chemical mapping of both active compound and excipients, as well as for visualization of solid form variation in the final product. The suggested NIR-CI approach is a promising process control tool for characterization of innovative patient-centred medicinal products.

Particle size is a critical parameter during tablet production as it can impact tabletability, flowability, and dissolution rate of the final product. The purpose of this study was to investigate the effect of initial particle size on fragmentation of pharmaceutical materials during tableting. Initial particle size fractions ranging from 0-125 to 355–500 µm of dibasic calcium phosphate (DCP), lactose monohydrate, and agglomerated and non-agglomerated microcrystalline cellulose (MCC) were blended with magnesium stearate and compressed into tablets. Larger initial particle sizes were found to fragment more extensively than smaller initial particle sizes for all materials based on the particle size distributions determined by laser diffraction. DCP was found to fragment most extensively followed by lactose and both MCCs. The fragmentation degrees of DCP, lactose, agglomerated and non-agglomerated MCC reached 95, 81, 32, and 29%, respectively. These findings were further supported by an increase in specific surface area with increasing compression pressure of compressed particles. The NIR spectral baseline offset from tablets was found to increase with increasing compression pressure up to 50 MPa for all materials, which was the same compression pressure range where fragmentation was observed. The NIR spectral slope from tablets as a function of compression pressure furthermore showed a similar trend as the tabletability profiles. NIR spectroscopy can thereby potentially be used as a surrogate control strategy for assessing compression related particle size changes and possibly tablet density and deformation behavior during tablet production.